MANAGMENT OF STAGE IIIA NSCLC REMAINS CONTROVERSIAL

Expert Rev Anticancer Ther. 2008;8(12):1913-1929. ©2008 Expert Reviews Ltd.

Posted 01/07/2009

Abstract and Introduction

Abstract

New developments in the management of non-small-cell lung cancer, as well as recent proposals for changing the current lung cancer staging system, are posing a challenge in the therapeutic decision making regarding this disease. For the last two decades, the management of stage IIIA (N2) disease has been controversial and the target for clinical trials has been to determine the best therapeutic approach that may result in better survival outcomes without increasing toxicity. For many years, combined modality treatment (systemic chemotherapy plus radiation therapy) became the standard of care in this setting. However, the poor outcomes seen with combined modality for N2 has obligated us to explore other possibilities. In this sense, recent clinical trials in the neoadjuvant setting using chemotherapy alone or combined modality are providing fruitful results and shifting the paradigm on this stage. A recent, large randomized multicenter trial argues against what has slowly become a current practice in some centers - the use of preoperative modality for N2 disease. Another controversy that we will discuss here is the acceptance of adjuvant therapy for resected stage IB-IIIA non-small-cell lung cancer. It was not long ago that adjuvant radiation therapy was still the standard of care for patients who have pathological nodal disease. We will present the current data on these debatable issues and how to implement this new knowledge into clinical practice.

Expert Commentary

The management of clinical N2 poses a challenge today due to novel therapeutic agents with a better toxicity profile, better RT-delivery methods and extensive data with provocative and controversial results from our clinical trials. The latter issue causes difficulty in interpreting trial results that do not subdivide patients appropriately. Thus, what is better: to offer neoadjuvant therapy (single or combined modality) followed by surgery or postoperative (adjuvant) CT? To date, we have not reached a final answer. We have meta-analyses, subanalyses and provocative observations that served as the platform for the new generation of clinical trials. A new lung cancer staging classification has been proposed (IASLC Lung Cancer Staging Project) and, if accepted, it means that we will be more aggressive in the management of this disease, and exhaust all possibilities to consider a patient a potential surgical candidate.

To answer the question of what is better, neoadjuvant or adjuvant CT in NSCLC, perhaps we will need to wait for the final results of the NATCH trial initially presented at the World Lung Cancer Congress in Seoul, Korea.^[84] This three-arm trial will address the question of whether DFS is improved with the use of neoadjuvant or adjuvant CT compared with surgery alone in early-stage NSCLC. Unfortunately, this trial does not include N2 disease, only clinical stages I (> 2 cm), II and T3N1. Patients are randomized to surgery alone or three cycles of neoadjuvant carboplatin/paclitaxel or surgery followed by three cycles of adjuvant carboplatin/paclitaxel (at the same schedule). This prospective, randomized trial planned to include 624 patients and mature survival data are expected in 2009.

Is single modality superior to combined modality for N2? To date, the ACCP does not recommend the use of combined modality (for downstaging) outside the context of clinical trials.^[19] Although this approach has shown clinical efficacy, there is concern in terms of toxicity and long-term results, and we still do not know what is the best CT combination and RT dosing and schedule. The vast majority of the data favored neoadjuvant CT (at least three cycles) rather than combined modality.^[30,32,85] When CT has been used as a single modality, the rate of progression was low for those who underwent neoadjuvant treatment and surgical results were also comparable to those randomized to surgery alone.^[32,85] A caveat on these studies^[30,32] is that they did not include N2 disease (stage IIIA was defined as T3N1). A systematic review that included seven clinical trials comparing preoperative CT followed by surgery versus surgery alone favored the neoadjuvant arm (HR: 0.82).^[86] When the EORTC 08012 was added to this population, the HR still favored neoadjuvant CT but to a lesser extent (HR: 0.88).^[85] In terms of preoperative concurrent CT/RT, a subanalysis from the INT 0139 suggested that, if pneumonectomy is planned ahead, perhaps this approach (trimodality) is not recommended due to the high mortality rate seen in this group; hence, the importance of a multidisciplinary approach among the treating physicians.

Presently, we consider there to be enough data to avoid the use of postoperative RT in patients with pathologic early-stage NSCLC. These patients are well served with cisplatin-based doublet adjuvant CT. As mentioned previously, we lack strong evidence for pN2 disease. However, a subset analysis from the ANITA trial showed that sequential adjuvant CT followed by RT results in a better outcome for these subjects.^[22] Thus, in this regard, we consider that the use of RT in this setting will be at the discretion of the treating physician.

The trimodality option studied in the INT 0139 trial needs longer follow-up to analyze the morbidity and mortality, especially when a pneumonectomy is performed. A concern for the trimodality approach is that those patients who are not candidate for surgical resection after induction will face a suboptimal treatment since RT is restarted after several weeks taken for restaging for possible surgery. This gap in the treatment delivery is associated with poor outcomes.^[87,88] Thus, this approach is better served in a multidisciplinary approach and a case-by-case basis.

Five-year View

Thus far, the management of clinical and pathologic N2 disease represents a challenge and debate in oncology. Several ongoing clinical trials will, in the near future, define the best combination of conventional and/or targeted agents either as a single modality or in combination with RT. We are waiting for the impact that targeted agents may have in early-stage NSCLC. The positive results found in ECOG 4599 in the metastatic setting created the background to move this agent into the adjuvant setting.^[89] Such a study (ECOG 1505) is already ongoing for stage IB-IIIA NSCLC. The results of the NATCH trial are eagerly anticipated and we hope that it will define the role of neoadjuvant versus adjuvant treatment for NSCLC.

There are a lot of expectations of what changes may occur if the lung cancer staging system is modified in the near future. Several studies have shown that our current staging system does not discriminate sufficient among lung cancer patients within the same stage.^[90,91] N2 disease encompasses a large heterogeneity, and it will be very important for future trials to better define and measure this specific disease stage. Certainly, the use of PET, re-mediastinoscopy and endoscopic ultrasound will play a more important role in the restaging process of patients after induction treatments, and perhaps will replace the conventional computed tomography for this purpose.^[92]

Many questions remain unanswered. Unfortunately, the North American Intergroup trial (S0332/RTOG 0412) was closed prematurely, and hence, has left us without an answer for the controversial IIIA (N2) disease in terms of best induction treatment: CT alone versus combined modality. Thus, the results of a Phase II trial conducted by the Korean NCI: (looking at the same concept) are eagerly awaited for the significant importance that they have to better understand this disease.^[103]